Spondylodiscitis in Pediatric Age: A Retrospective Cohort Study

Background: Pediatric spondylodiscitis is rare, hardly diagnosed and treated due to the nonspecificity of clinical presentation and laboratory investigations, difficulty of etiologic identification and lack of management guidelines. Methods: A retrospective study was conducted on 29 children with spondylodiscitis. Clinical, hematic and radiologic data were collected and compared between 2 age-subgroups (below and from 4 years old on) to investigate age-related differences. Epidemiologic, management and follow-up data were also described. Results: Slight male predominance and a peak of incidence <2 years were observed. Symptoms were significantly differently distributed in the 2 age-subgroups: children <4 years showed mainly refusal/inability to sit or bear weight, irritability, limping and poor general conditions; children ≥4 years most frequently had back pain and fever, and pain upon palpation of the spine. The lumbar spine and more than 1 vertebra were most frequently involved. Median diagnostic delay of 12 days was observed, without significant difference between age-subgroups, and delay >2 months was always associated with multivertebral involvement and complications. All children were treated with broad-spectrum antibiotics for a median of 12 weeks. Only in 1 complicated case, surgical treatment was also required. Conclusions: The clinical presentation of spondylodiscitis may be age-specific, with younger children often exhibiting subtle signs and symptoms. Broad-spectrum antibiotics covering for Staphylococcus aureus should be initiated as soon as possible and performed many weeks, being effective in treating the infection without clinical sequelae, even in patients with comorbidities. Surgical treatment should be reserved for complicated cases with neurologic involvement.

S pondylodiscitis describes a continuum of spinal infections, including discitis, vertebral osteomyelitis and spondylodiscitis itself, in which both the intervertebral disc and one or more vertebrae are involved. 1,2pondylodiscitis is rare in children, with an incidence of 0.3 versus 2.4 per 100,000 in adults, 3,4 representing only 3% of osteoarticular infections in pediatric hospitals. 5The first peak of incidence is observed in children 6 months-4 years of age, with a second peak in adolescents.Sporadic cases are reported in infants under 6 months of age. 6Spondylodiscitis is commonly acute (days/weeks) and caused by pyogenic bacteria, less often subacute/chronic (months/years) and mainly of tubercular origin. 7,80][11] Early diagnosis of pediatric spondylodiscitis is challenging, with diagnostic delays of up to 3 months due to its rarity and nonspecific onset. 12Blood tests are also nonspecific, with often normal white blood cell (WBC) count and slight increases in C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR). 13Blood cultures show low sensitivity in most series. 6,12When etiological agents are isolated in culture, pyogenic bacteria are usually found, mostly Staphylococcus aureus, with methicillin-resistant S. aureus (MRSA) becoming more prevalent. 14Subacute/chronic spondylodiscitis is typically caused by nonpyogenic bacteria like M. tuberculosis, which is the most common cause of pediatric spondylodiscitis in developing countries. 15Conventional radiographs have low sensitivity, especially in the early stages of the disease.Magnetic resonance imaging (MRI) represents the standard for diagnosis, with high sensitivity and specificity. 16Bone biopsy can be performed when neoplasm cannot be excluded by imaging, antibiotic therapy is not effective or complications are present.Currently, there are no guidelines outlining the best therapeutic approach in childhood, while treatment guidelines for adults have been published. 17If not promptly diagnosed and adequately treated, spondylodiscitis can lead to severe orthopedic and neurological complications. 1 In this retrospective study, we describe a series of pediatric spondylodiscitis cases.The aim of the study is to define the epidemiologic, clinical, radiological and microbiologic data of pediatric spondylodiscitis, and to search for age-related differences that could help in its diagnosis and management.

METHODS
A retrospective study was conducted on children with spondylodiscitis hospitalized at Meyer Children's University Hospital (Florence, Italy) from January 2010 to December 2021.Epidemiological and clinical findings, blood parameters, including WBC, ESR, CRP, microbiologic tests (either on blood or on bone biopsy by culture or real-time or broad-range polymerase chain reaction [PCR] assay or other), radiologic results, management, including type and duration of medical and surgical therapy were collected.Follow-up data including duration and outcome were also reported.The cohort has been divided into 2 age-subgroups (under and from 4 years old on) to investigate age-related differences, based on our sample age distribution and preexisting demographic data.Two cases of tuberculous spondylodiscitis were found and excluded due to the substantial differences with pyogenic spondylodiscitis.Statistical analyses were performed using IBM Statistical Package for Social Science software (SPSS, Version 28.0, Chicago, Illinois, USA).Data were reported as medians and interquartile ranges (IQR) for continuous variables and as percentages for categorical variables.The nonparametric Mann-Whitney U test was used for analyzing the differences in continuous variables between 2 groups of and the χ 2 test was used for categorical variables.Values of P < 0.05 were considered statistically significant.

RESULTS
Table 1 shows the details of the epidemiologic, clinical, hematologic and microbiologic characteristics of each patient.

Epidemiologic data
Twenty-nine children, 19 (66%) males, with a median age of 3.2 years (IQR 1.7-11.5),were included; 15 (52%) were under the age of 4 years.A peak of incidence was observed in children <2 years (N = 12, 41%), with a subsequent homogenous distribution of cases with increasing age, and a slight increase in those who were over 10 years old (Fig. 1).Comorbidities were present in 7 (24%) patients: Arnold-Chiari type 1 malformation in 2 cases, immunosuppression in an infant with neutropenia, bronchopneumonia and neuroenteric cyst, and lumbosacral myelomeningocele with pressure sore, tetraparesis, polycystic kidney disease and dystonic movement-behavior disorder were present each in 1 patient.A previous trauma was referred in 7 (24%) patients and a recent infection was reported in another 24%; 4 patients had domestic cats.
Definitive diagnosis of spondylodiscitis was ascertained after a median of 12 days (IQR 8-17) from the clinical onset, with no significant difference in the 2 age subgroups.The diagnostic delay was greater than 2 months in 4 patients.Twenty-three patients (79%) had already been evaluated by a doctor for the same symptoms, before actual admission.

Laboratory Workup
A normal WBC count on admission was present in 25 (86%) patients, with a median value of 9060/mm 3 (IQR 7240-11,090).CRP was slightly elevated in most patients (N = 22, 76%), with median value of 1.57 mg/dL (IQR 0.66-2.23,normal value 0-0.5) and ESR was altered in most subjects (N = 21/27, 78%) with median value of 50 mm/h (IQR 24-71, normal value 0-20).No significant differences between age subgroups were observed in any hematological parameter.Five patients presented hypochromic microcytic anemia, and 4 were under 4 years old.Overall, microbiologic tests were positive in seven (24%) cases.Blood culture was collected in 12 (41%) patients; only 2 (17%) tested positive, both with isolation of Panton-Valentine Leukocidin-negative, methicillin-sensitive S. aureus (MSSA).S. aureus was isolated in the other 2 cases, 1 MRSA by culture on surgically drained material and 1 MSSA (together with S. agalactiae) by PCR on a pressure sore swab.Bartonella henselae was found on PCR on surgically www.pidj.com| 533 Spondylodiscitis drained material and on serology in 1 child, Salmonella spp. on stool culture in another subject, and S. pneumoniae on PCR on a pharyngeal swab in another.PCR on blood samples was performed in 22 (76%) patients, all with negative results.In 3 patients (10%) a biopsy of vertebral pathological tissue was undertaken, 1 of them without etiological identification, the other 2 identifying the previously described MRSA and Bartonella spp.

Imaging Features and Complications
Radiological characteristics in our cohort are shown in Table 3. Spine radiography was the first radiological examination in 21 (72%) patients; 8 (38%) showed spinal alterations: in detail, physiologic lumbar lordosis was increased in 2 patients and decreased in other 2, and reduction of the intervertebral disc space was present in 4. Spine MRI was the diagnostic investigation in all cases.The median time between spine radiograph and MRI was 2 days (IQR 0-7).When the radiograph was altered, MRI was performed after a median latency of 1 day (IQR 0-3), whereas it was 5 days (IQR 0-15) if radiographs were normal.Spine CT, performed in 7 (24%) patients, was diagnostic in 6 (86%) cases.Technetium-99m bone scan was performed in only 1 patient and showed areas of increased tracer absorption.
In 21 cases (72%) at least 2 vertebrae were affected.The 2 patients with 3 or more affected vertebrae had a diagnostic delay of   7) 1 (7) 0.501 patients presented complications.The most frequent ones were paravertebral (N = 10, 34%) or epidural (N = 4, 14%) abscesses, with the secondary displacement of the psoas muscle by paravertebral abscess in 2 (7%) patients and secondary spinal cord compression by an epidural abscess in 1 (3%), detected on MRI.Kyphosis developed in 2 (7%) patients, always associated with vertebral collapse or destruction.

Follow-up and Outcome
At discharge, only 7 (24%) patients reported residual symptoms, mainly mild back pain with mobilization and slight limping.One patient was lost at follow-up.All other patients underwent follow-up at the infectious disease outpatient unit for a median of 2 months (IQR 1-4.5) after the end of antibiotic therapy and 9 of them (32%) also had an orthopedic follow-up for a median of 19 months (IQR 14-29).Complete remission of symptoms occurred in all cases during follow-up.Radiologic follow-up was performed in 13 (46%) patients with spine MRI and radiography, in 14 (50%) patients with MRI alone, and in 1 (4%) with radiography alone.At the last radiologic follow-up, which occurred after a median of 12 months (IQR 8.5-29), complete normalization occurred in 4 (14%) patients; the remaining 24 (86%) showed minimal residual features during follow-up, which were not clinically relevant.None of our patients reported clinical sequelae at the end of follow-up nor experienced disease recurrence.

DISCUSSION
Spondylodiscitis is a rare diagnosis in the pediatric age, undermining the lack of pediatric management guidelines and the frequent diagnostic delay.Our study represents one of the largest case series published in the literature, despite describing a relatively small cohort of 29 patients.
In accordance with other studies, 6,12 in our cohort a slight male predominance was found.In larger series, a bimodal age distribution for this condition is reported, 6 while in our study a high peak of incidence in young children (<2 years) was identified, with a median age at diagnosis of 3.2 years.By dividing our cohort into 2 age subgroups, distinct clinical pictures and pathophysiological mechanisms for each were observed: older children showed a typical clinical pattern characterized by higher fever and back pain, whereas in the younger ones, symptoms were subtle and mainly included irritability, refusal to bear weight, difficulty in changing position and deterioration of general conditions.This age-specific symptom distribution is widely reported in the literature. 6,9,18Due to clinical nonspecificity, misdiagnosis of spondylodiscitis is not uncommon; inflammatory arthritis, bone tumors and fractures are the main differential diagnoses.
Furthermore, routine blood tests are of little help in the diagnosis according to the literature. 10,19Also in our series, most patients showed normal WBC counts, whereas increased ESR was the most frequent inflammatory marker at diagnosis, and its normalization was observed before discharge in all patients but one, suggesting a possible correlation with antibiotic response.
Initial radiological examination with spine radiograph, performed in most patients, was negative in more than half.Suspicious radiograph findings led to earlier MRI performance, which was still required for diagnosis confirmation and complications detection.Suggestive features on MRI were reduced intervertebral disc height, disc hypointensity on T1-weighted images, disc hyperintensity on T2-weighted images or enhanced disc contrast.The lumbar spine was the most involved site, confirming previous pediatric data. 20The nonspecificity of symptoms and routine blood tests, along with frequent normal radiographs, contribute to the diagnostic delay, which was from about 2 weeks to up to 4 months, in our cohort.These data are in agreement with other series, 13,21,22 however, Chandrasenan et al 13 reported a greater diagnostic delay in children under 24 months, which was not observed in our cohort.
A delayed diagnosis could imply more extensive bone infarction and consequent vertebral wedging/collapse, which can result in spinal instability and risk of spinal cord compression, especially in neonates and infants <6 months of age.Infection can spread to surrounding soft tissues causing paravertebral abscesses, or to the epidural and subdural space causing abscesses or meningitis. 2 In our series, paravertebral and epidural abscesses were the most common complications.Two of the four patients with long diagnostic delay had three or more involved vertebrae and complications.Pyogenic bacteria can reach the spine by the hematogenous route, by direct inoculation during a procedure or trauma, or by spreading from contiguous tissues.The most frequent mechanism in childhood is the hematogenous spread of a distant infectious focus, and a history of recent upper/lower respiratory tract infection or diarrhea is common.Many infants develop spondylodiscitis as a consequence of neonatal sepsis. 18,23In our cohort, comorbidities were reported in 24% of patients, and the patient with the most severe clinical picture was a neutropenic infant with previous pneumonia who developed severe complications.A history of trauma was present in 24% of our patients, similarly to other published reports. 24Recent infection was also variably reported in the previous series, in up to half of the cases according to Chandrasenan et al 13 and Garron et al 21 , and was present in another 24% of our patients.Hematogenous spondylodiscitis usually develops starting from the vertebral body metaphyseal plate, which is highly vascularized in young patients; in older children, the intervertebral disc becomes progressively avascular and, therefore, bacterial infection directly locates in the vertebral body. 12,25,26Accordingly, in our cohort disc involvement was present in all children <4 years.
Etiological differences have become evident thanks to the availability of new diagnostic techniques.K. kingae has been recognized as the second leading cause of spondylodiscitis in children 6 months-4 years old, after S. aureus. 12However, in our series, this pathogen has not been identified.Blood cultures, collected in a few patients, were positive only in 2, both for S. aureus.According to the literature, the most frequently isolated pathogen was S. aureus, in 1 case MRSA; other isolates were B. henselae, Salmonella and S. pneumoniae (the last 2 with uncertain causative roles).Overall, microbiological investigations (by culture and PCR assays on different materials) allowed to identify the putative causative agent in 24% of patients, accordingly to other studies, where etiological identification rate ranges between 0% of Kayser et al 11 , Karabouta et al 27 and Scheuerman et al 28 series and 44% of Chandrasenan et al 13 Garron et al 21 and Kang et al 4 reached higher identification rates (52% and 88%, respectively) due to the high number of biopsies performed in their cohorts (83% and 92%, respectively). 4,21In our series, biopsies were performed in 3 patients and were diagnostic in 2. Considering the good outcome of our patients after broad-spectrum antibiotic therapy, even in those without an etiological diagnosis, we confirm that the biopsy approach should be reserved for complicated and unresponsive cases requiring surgical treatment.All patients were treated with broad-spectrum antibiotic therapy administrated iv for a median of 4 weeks and then orally for an overall median duration of 12 weeks, similarly to what was reported in older studies. 29,30Other pediatric series reported a shorter duration of treatment, of 4-6 weeks overall. 4,20,27,28,31The most used iv agents in our cohort were oxacillin and third-generation cephalosporins, followed by teicoplanin.The most frequently administered oral antibiotics were semisynthetic penicillins and first-generation cephalosporins.In most of our cases, this management led to complete recovery without sequelae or relapses.Only 1 case has been also subjected to surgical treatment, with resolution.We, therefore, agree that empirical therapy should be based on iv broad-spectrum antibiotics covering for S. aureus, for at least 2 weeks, followed by several weeks of oral therapy; surgery should be reserved for cases with neurological signs of bone marrow compression.
The main limitations to this study are the retrospective design and the small sample size.Due to the data retrieval and collection method, some follow-up data were lost for patients hospitalized before 2018.Radiological follow-up was performed in all but 1 patient, with minimal residual findings in most of them.Clinical follow-up was performed in all patients at the infectious disease unit for about 2 months after antibiotic withdrawal; orthopedic follow-up was available for one-third of the patients.Despite the presence of comorbidities in approximately 24% of our patients, clinical remission was always obtained without clinical sequelae or relapse.
In conclusion, our study suggests that the clinical presentation of spondylodiscitis may be age-specific, with younger children often exhibiting subtle signs and symptoms, which should be taken into consideration in the diagnostic process.Treatment with broad-spectrum antibiotic therapy covering for S. aureus should be initiated as soon as possible; the duration of iv and oral antibiotic therapy should be tailored according to clinical and laboratory alterations.Patients with comorbidities and/or complications could require longer regimens.Surgical treatment should be reserved for complicated cases with neurological involvement.More studies are needed in pediatrics for the establishment of international diagnostic criteria and treatment recommendations.

TABLE 2 .
Clinical Presentation of All Patients (n = 29), Divided by Age Subgroups

TABLE 3 .
Radiological Characteristics of All Patients (n = 29), Divided by Age Subgroups